Project 1 is central to the overall Children's Environment and Disease Prevention Research Center at Dartmouth. Accumulating data suggest a variety of adverse effects that may result from arsenic exposure during the vulnerable window of fetal development and early childhood. Altered immunity is among the key pathways identified as affected by arsenic in experimental studies and in highly exposed populations. However, such studies do not exist for the US at levels relevant to our population. Infections are the most common causes of illnesses in children in US, and are the leading causes of deaths in children worldwide. Additionally, allergy and atopy have become a more widespread source of childhood morbidity in recent years for reasons as yet unknown. Our preliminary data from animal and epidemiologic studies provide both mechanistic and clinical evidence of aberrant immune function related to arsenic exposure in infants. Recent studies also suggest a significant impact of certain environmental exposures on vaccine response in children, but the effects of arsenic on vaccine response have not been investigated. Further, new technologies are just beginning to uncover the fundamental role of the establishment of the intestinal microbiome early in life on immune system maturation and competency as well as in metal biotransformation. We propose to build on a prospective cohort study to determine whether prevalent exposure levels of arsenic influence children's immune response including risk of infection, allergy/atopy, vaccine response and intestinal microbial acquisition. The longitudinal birth cohort study comprises 1,000 mother-child dyads who are residents of New Hampshire and obtain household water from private wells, a potential source of arsenic exposure in the region. We will actively follow infants enrolled in the cohort through: (1) interval interviews with the mothers every four months and (2) screening pediatric records up to age 5 years. We will request a venous blood sample from infants during their one-year.well-child visits to test for antibody response to diphtheria/tetanus/pertussis, pneumococcus and polio vaccines in collaboration with Dr. Kari Nadeau at Stanford University. As an exploratory aim, we will sequence bacterial DNA from repeated stool samples (collected at six weeks and 12 months of age) to assess the relation between in utero and early life exposure to arsenic on the developing microbiome. To our knowledge, this is among the first prospective molecular epidemiologic studies of arsenic and children's health in the US, and among the few cohorts in the US with detailed early childhood infection information along with other immune-related variables.